This proposal aims to investigate the atrial natriuretic peptide (ANP) and its receptor, NPRA, as candidate genes for asthma, a common chronic inflammatory lung disease to which about 4000 individuals succumb each year in this country. The complexity of asthma is reflected in the large number of genetic factors that can make up a specific asthma phenotype. The genes contributing to asthma are thought to be susceptibility loci that influence, but do not determine, the overall disease risk. It is plausible that genes that determine the overall disease risk are yet to be identified. ANP, the C-terminal peptide of pro-ANP, plays a pivotal role in the development of thymocytes in embryonic and neonatal mice and promotes a T helper type 2 (Th2)-dominant response in the lungs of adult mice and therefore may contribute to the genesis and progression of asthma. NPRA deficient mice are protected from asthma. The ANP-NPRA pathway is involved in directing human DCs to promote Th2-dominance and human mast cells to release mediators in both an IgE-dependent and - independent manner. A preliminary association analysis of 4 SNPs of NPPA gene were typed in 488 patients with well-characterized asthma (cases) and in 186 healthy controls without asthma shows that there is a significant associations for asthma between a common haplotype (CGTG) in both African Americans and Caucasians. These findings have led to the hypothesis that NPPA and NPR1 are important susceptibility loci for asthma and that there are specific polymorphisms associated with different atopy (e.g., total serum IgE) and asthma (e.g., bronchial hyperreactivity) phenotypes. The primary goal of this submission is to determine if polymorphisms in the gene for ANP, NPPA, and the NPRA receptor gene, NPR1, are associated with asthma. We hypothesize that NPPA and NPR1 are important susceptibility loci for asthma and that there are specific polymorphisms associated with different atopy (e.g. total serum IgE) and asthma (e.g., bronchial hyperreactivity) phenotypes. To test this hypothesis, the following specific aims are proposed. In Aim #1, it is planned to determine the association between genotype and haplotype SNPs (htSNP) in ANP (NPPA) and NPRA (NPR1) genes in asthmatics and matched healthy controls in a population of African-Americans and Caucasians. The associations among haplotypes in 714 subjects with asthma and 500 controls matched for age, ethnicity, BMI and gender will be examined using DNA collected from several clinical trials from the American Lung Association, Asthma Clinical Research Centers (ALA-ACRC). Additionally, the htSNP approach will be used to capture genetic variability in association analyses. In Aim #2, it is proposed to investigate whether pro-ANP (I-98) can be biomarker of asthma and/or atopy. It is planned to use serum samples from a subgroup of well-characterized allergic/asthmatic subjects (n = 714 cases and 500 controls), collected through ALA-ACRC asthma studies. Thus, serum levels of pro-ANP will be measured by an established EIA and correlated with genotype and haplotype SNPs studied in aim#1 with disease severity of these patients and with total IgE estimated in the same serum samples. These results will indicate whether ANP can be biomarker for asthma. The analysis of polymorphism in this novel candidate gene for asthma is expected to increase our knowledge of NPPA and NPR1 genes which play a critical role in several common human diseases including asthma. PUBLIC HEALTH RELEVANCE: The incidence of asthma and the rates of hospitalization, health care utilization and mortality because of asthma are increasing worldwide. Although better management has decreased asthma mortality in this country, about 4000 individuals will die each year from asthma. Asthma is the most common disease of childhood. African American children and young adults are three to four times more likely than whites to be hospitalized for asthma and four to six times more likely to die from asthma. Asthma is a complex disease and this complexity is reflected in the large number of genetic factors that can make up a specific asthma phenotype. This proposal aims to investigate the association of polymorphism of a positional candidate gene, ANP and its receptor, which appear to play a critical role in pathogenesis of many inflammatory lung diseases including asthma and chronic obstructive pulmonary diseases. The existing results indicate that inhibiting this pathway might be therapeutic for asthmatics. Establishing an association of ANP polymorphisms will not only confirm the importance of this gene in asthma, but may also indicate who will benefit from an ANP-based therapy.